Tuberculostatic agent



Patented May 4, 1954 UNITED STATES PATENT 2,677,641 OFFICE TUBERCULGSTATIG AGENT No Drawing. Application January 18, 1952, Serial No. 267,192

7 Claims. 1

This invention relates to new medicinal agents useful for the treatment of tubercle bacilli infec tions and methods of employing the same.

Only two therapeutic materials, streptomycin and p-aminosalicylic acid, have been employed widely in the treatment of tubercle bacilli infections. Neither of these materials is usually considered to be a complete cure for such infections; they simply stay the progress of the infection and are therefore referred to as tuberculostatic materials. Of the above two mentioned materials, streptomycin is usually considered to be of greater primary effectiveness and is often employed as the sole therapeutic material in tubercle bacilli infections. Streptomycin presum ably could be employed to maintain a static condition in the tubercular patient for an indefinite period were it not for the fact that drug-resistant strains of tubercle bacilli develop, which bacteria are not appreciably affected by streptomycin therapy. For this reason prolonged treatment with streptomycin as the sole therapeutic agent is often discouraging. Because of the above property of streptomycin in the treatment of tuber cular infections, p-aminosalicylic acid, otherwise known as PAS, has gained widespread usage as an auxiliary agent to be employed in combination with streptomycin. While PAS is not sufficiently active to be employed as the only drug in combating tubercle bacilli infections, its use with streptomycin does, in some instances at least, prevent the formation of drug resistant strains.

As may be seen from the preceding description, streptomycin and PAS leave much to be desired in the way of therapeutic materials for the treatment of tubercle bacilli infections. Of course, a therapeutic material sufficiently active to eradicate tubercle bacilli infections would be indeed desirable but until such a material can be found, additional tuberculostatic materials effective against streptomycin resistant strains, or which cause the development of strains against which streptomycin iseffective, would be highly useful and a great benefit to humanity. The present invention makes available such a medicinal agent having a substantial tuberculostatic activity and which has the additional advantage that it may be given orally.

The new medicinal agent of this invention comprises dosage units of pyrazinamide or its equivalent salts. Pyrazinamide is a known chemical compound which may be prepared by methods to be found in the chemical literature. Clinical tests have demonstrated that dosage units of pyrazinamide may be safely employed with beneficial results in the treatment of tubercle bacilli infections in human patients. This new medicinal agent is, for instance, of value in treating infections where strains of bacilli have developed which are resistant to streptomycin therapy, since strains of tubercle bacilli which are resistant to streptomycin therapy are not always resistant to treatment with dosage units of pyrazinamide. Another instance when the treatment of tubercular patients with dosage units of pyrazinamide is of special value is during rest or collapse therapy. As is well known to those skilled in the art, in many instances the attending physician hesitates to employ streptomycin unless rest and collapse therapy have failed because, as a precautionary measure, the physician may wish to save streptomycin therapy as a last resort for use when all other measures havefailed. The instant invention therefore gives to the physician a medicinal agent which he can employ during or before rest therapy without, in most instances, decreasing the effectiveness of streptomycin therapy. In the above instances, dosage units of pyl'azinamide may be employed as the sole therapeutic agent, or they may be employed in combination with other materials, for instance, PAS. Since pyrazinamide also causes drug resistant strains to develop in many instances, PAS may be employed simultaneously therewith for the same reason that it is sometimes employed along with streptomycin treatment.

A dosage unit of pyrazinami-de, for an adult patient, comprises from about milligrams to about 1,030 milligrams of pyrazinamide. A dosage unit for a child, of course, will be proportionally smaller and can comprise, for instance, from about 50 to 300 milligrams of pyi'azinamide depending upon the size of the child. In the treatment of tubercle bacilli infections, such dos-- age units are employed in such a manner that atotal of from about 1 to 8 grams or" pyrazinamide, for an adult patient, are administered orally in a tweny-four hour period. Latest clinical tests indicate that the preferred range for human adult patients is 3 to 5 grams of pyrazinamide in a twenty-four hour period given in dosage units of 200 to 700 milligrams of pyrazinamide. For instance, 10 to 15 capsules containing 350 milligrams each, or 6 to 10 tablets containing 500 milligrams of pyrazinamide per tablet can be employed in each twenty-four hour period with beneficial results. In children, the daily intake of pyrazinaniide may be reduced proportionally so that from about 5 to 40 milligrams per pound of body weight are administered in a twentyfour hour period. Such a daily administration of dosage units of pyrazinamide can be made for as long a period as desired, although, as has been previously mentioned, drug resistant strains of tubercle bacilli tend to develop and it is usually advantageous to discontinue treatment ail-er a few weeks. Treatment can then be continued, if desired, after a period of time. For instance, daily dosage units can be employed for a fourweek term followed in two weeks by a second four-week term, or alternatively, a single sixweek term can be employed. Of course, the

above periods are only a guide and may be varied to meet the peculiarities of a particular situation.

A preferred dosage unit form is a tablet containing pyrazinamide as an active ingredient. For adults such a tablet should preferably contain from about 300 to 700 milligrams, of pyrazinamide, but for children, from 50. to 300v milligrams per tablet is usually more satisfactory. Of course a larger tablet scored to be broken into dosage units such as previously described, or a number of smaller tablets adapted to be taken at one time to constitute a dosage unit, are also satisfactory. A second preferred dosage unit form is a capsule containing, as an active ingredient,

from 200 to 500 milligrams of pyrazinamide for 1 adults or from 50 to 300 milligrams for children. As will be noticed, the preferred dosage unit in capsule form is smaller than in tablet form and this is for the reason that in tableting the material is. compressed into a smaller volume than in capsuling. Such capsules may be of either the hard or soft variety and may be made of any suitable encapsulating material which will disintegrate in the digestive tract in from about 1 to 4 hours. Examples of such encapsulating materials are gelatin and methyl cellulose. Other dosage unit forms of pyrazinamide, such as granules, powders and pills, may also be employed.

Of course, the dosage unit of pyrazinamide may contain other inert or medically active materials. For instance, when the dosage unit form is a tablet, pill or granules, there may also be present various binders, fillers, or solid diluents. Suitable materials for this purpose may be illustrated by starch, for instance corn starch, and sugars, for instances lactose and sucrose. There may also be present various medically active materials, for instance p-aminosalicyclic acid. When the dosage unit form is a capsule, it may contain in addition to materials of the above type, a liquid carrier such as a fatty oil. And regardless of the dosage unit form, there may be present various flavors, for instance oil of wintergreen, and excipients, for instance dicalcium phosphate. Various other 'materials may be present as coatings, or to otherwise modify the physical form of the dosage unit. For instance, pills or capsules may be coated with shellac, sugar, or both. Of course, any materials used in preparing the dosage unit form must be pharmaceutically pure and substantially non-toxic in the amounts employed.

The following is a procedure which has been employed in the preparation of scored tablets containing 500 milligrams of pyrazinamide: To 50 parts of dry pharmaceutically pure pyrazinamide there is added parts of dry corn starch. This mixture is placed in a mixer and 8.5 parts of wet corn starch paste added. The resulting mixture is granulated and dried and an additional '1 dry corn starch added. There is added 0.3% magnesium stearate to prevent sticking and the mixture is then tableted in a tableting machine.

The blood level of pyrazinamide in a patient receiving a dosage unit form of pyrazinamide can be readily determined. A suitable method for such a determination comprises removing the blood color, cells and proteins from a sample of blood by tungstic acid precipitation, and treating the resulting extract to remove the excess tungstate and sulfate. The pyrazinamide in the extract is then hydrolyzed with alkali to the corresponding salt of pyrazinoic acid. Since pyrazinoic acid forms a complex with ferrous ions,

which complex has an orange-red color and absorbs light at a wave length of 480 millimicrons in accordance with Beers law, a purified solution of the salt of pyrazinoic acid obtained above can be treated with ferrous ammonium sulfate, and the optical density of the resulting orangered solution can then be read on a spectrophotometer. This optical density can be compared with that of prepared solutions of known concentration to determine the concentration of pyrazinoic acid complex in the unknown, and from this one can, of course, calculate the original concentration of pyrazinamide in the blood. By such a procedure it has been determined that blood levels of pyrazinamide, one to two hours after dosage units of the same have been ad ministered orally, are usually from 10 to gammas of pyrazinamide per milliliter. This checks very well with test tube experiments where it has been found that in the test tube the growth of tubercle bacilli is partially inhibited by the presence of 10 gammas of pyrazinamide per milliliter and completely inhibited by the presence of 100 gammas of pyrazinamide per milliliter. It is not intended, however, that the above method of determining blood levels oi pyrazinamide constitute a part of the present invention.

We claim:

1. A medicinal agent for treatment of tubercle bacilli infections comprising about 50 to 1,000 milligrams of pyrazinamide in dosage unit form.

2. As a new article of manufacture, a capsule of encapsulating material containing from about 50 to 500 milligrams of pyrazinamide.

3.. A capsule of encapsulating material for treatment of tubercle bacilli infections, said capsule containing a solid diluent with an amount of from. 50 to 500 milligrams of pyrazinamide sufficient to constitute a dosage unit treatment against tubercle "bacilli infections.

4. As a new article of manufacture, a tablet comprising from about 50 to 700 milligrams of pyrazinamide in a solid compact form suitable for use as a dosage unit in tubercle bacilli infections.

5. A tablet for therapeutic use containing a solid diluent and from 50 to 700 milligrams of pyrazinamide.

6. A tablet for therapeutic use in tubercle bacilli infections, said tablet comprising from 50 to 700 milligrams of pyrazinamide and sufficient starch to act as a binder and hold said tablet together as a unitary mass.

'7. A tablet for therapeutic use in tuber -.e bacilli infections, said tablet comprising from 50 to 700 milligrams of pyrazinamide and a quantity of binder sufiicient to hold said tablet together as a unitary mass.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,283,817 Martin May 19, 1942 FOREIGN PATENTS Number Country Date 347,451 Great Britain Apr. 50, 1931 566,653 Great Britain Jan. 9, 1945 OTHER REFERENCES Manufacturing Chemist and Manufacturing Perfumer, April 1949, volume XX, Number 4, page 185.

Lehmann: Rev. Gen. Sci, 1947, volume 54, Numbers 9-10, pages 222 to 230. 

1. A MEDICAL AGENT FOR TREATMENT OF TUBERCLE BACILLE INFECTIONS COMPRISING ABOUT 50 TO 1,000 MILLIGRAMS OF PYRAZINAMIDE IN DOSAGE UNIT FORM. 